Mycobacterium tuberculosis (Mtb) infects a third of the world's population (Dye and Williams 2010) and is transmitted by the aerosol route. Although the mechanisms whereby Mtb evades the host immune response are increasingly well understood (Russell, D. G. 2007), those by which Mtb engages the immune response to drive tissue destruction and hence transmission are relatively poorly characterized (Yoder et al 2004). The events underlying this immunopathology are not well defined, in part because the mouse, one of the most useful models ill which to study Mtb immunology, does not develop lung pathology similar to man (North and Jung 2004, Young, D. 2009).
The microscopic pathology caused by Mtb in man has been described as “caseous necrosis” for over 100 years, because of the accumulation of cheese-like material in the centre of TB granulomas. Lung infection leads to cavitation, which is the development of air-filled spaces within the lung where the parenchyma has been completely destroyed. Mtb then proliferates exponentially in the cavity, essentially walled off from the host immune response (Kaplan et al 2003), and each cavity may contain up to 109 mycobacteria (Heike et al 2006). The current paradigm of TB pathology states that accumulating caseous material erupts into an airway, creating a cavity within which the Mtb proliferates freely. This paradigm was developed from the rabbit model during seminal work in the 1960s by Lurie and Dannenberg (Dannenberg and Sugimoto 1976) and is repeated unchallenged as conventional wisdom in current TB reviews (Cooper, A. M. 2006, Russell et al 2010a, Russell et al 2010b, Russell, D. G. 2007, Russell et al 2009, Barry et al 2009). The observation that that human cavities seem to start in areas of lipoid pneumonia, not in well organized granulomas, in a series of post-mortem studies has generally been overlooked (Hunter et al 2007). More recent conceptual models of TB immunopathology propose a TH1/TH2 imbalance (Dheda et al 2005), an excessive IL-17 response (Desvignes and Ernst 2009) or a failure of regulatory T cells to limit immunopathology (Guyol-Revol et al 2006), but none address effector mechanisms of tissue damage.
Tuberculosis (TB) continues to kill over 1.5 million people a year (Dye and Williams 2010). Standard treatment for TB has remained unchanged for over 30 years (Chan and Iseman 2002) and multi-drug and extensively drug resistant strains are progressively emerging (Wright et al 2009, Shin et al 2010). Mortality rates remain high amongst patients even after they have commenced TB treatment (Gandhi et al 2010, Yew et al 2010). A characteristic hallmark of TB is tissue destruction, causing morbidity, mortality and transmission of infection. However, the mediators of this immunopathology are incompletely understood (Cooper, A. M. 2009, Anandiah et al 2011), preventing the design of rational therapies to reduce immune-mediated host damage and improve outcomes in TB.
TB is primarily a disease of the lung (Frieden et al 2003, Schwander and Dheda 2011). In advanced HIV infection with severely reduced CD4 cell counts, TB infection is common but there is reduced tissue destruction and cavitation rarely occurs (Kwan and Ernst 2011). The underlying cause of divergent pathology in HIV-TB co-infection is poorly defined, and greater understanding of this tissue destruction may identify novel therapeutic approaches to limit morbidity and mortality.